Discovery and Optimization of Novel Integrase Inhibitors as Anti-HIV Agents

描述(申请人提供)：针对HIV病毒转录酶或蛋白酶的药物被用于高效抗逆转录病毒疗法(HAART)鸡尾酒，延长了艾滋病患者的生命。不幸的是，这些药物具有严重的毒性，在一些患者中无法控制病毒复制，并且由于病毒耐药性而有效。整合酶对HIV复制的绝对要求，以及它没有宿主细胞对应物的事实，使其成为一个有吸引力的药物开发目标。最近推出的整合酶靶向药物Raltegravir证实了这种酶是一个非常有前途的HIV/AIDS治疗靶点。我们对具有新型生物等位取代β-二酮基酸的HIV整合酶小分子抑制剂的研究，导致了新的具有个位数微摩尔效力的HIV整合酶抑制剂的鉴定。我们建议进行铅优化，以提高其效力，并评估其治疗艾滋病毒感染的潜力。我们将把药物化学与计算机辅助药物设计和生物测试结合起来，进行有效性、选择性和毒性的测试。将应用对接、分子动力学模拟、基于结构的设计、化学信息学、药效团测绘和三维定量构效关系(3D-QSAR)、并行组合合成、使用重组野生型和突变艾滋病毒整合酶变体的生物分析、针对病毒复制的细胞培养测试(包括来自艾滋病患者的抗药性分离株)的创新集成。感染HIV-1的人外周血单个核细胞(PBMC)培养将被用来测试化合物阻止HIV复制的能力。化合物的毒性将使用未感染的PBMC以及CEM白血病和Vero细胞进行测试，以评估治疗指数。该项目的成功将为临床前HIV/AIDS药物开发提供新型的“类药物”整合酶抑制剂；并增加我们在设计新型HIV整合酶靶向抗病毒药物方面的知识。与公共卫生相关：这项赠款提案寻求开发新的化合物，用于抑制艾滋病毒整合酶治疗艾滋病。PI已经发现了有效的整合酶抑制剂。赠款提案的目标是优化活性和测试毒性。

DESCRIPTION (provided by applicant): Drugs targeting the HIV virus transcriptase or protease are used in highly active antiretroviral therapy (HAART) cocktails that have prolonged the lives of AIDS patients. Unfortunately, these drugs are associated with severe toxicities, unable to control viral replication in some patients, and are rendered in effective by viral drug resistance. The absolute requirement of the integrase enzyme for HIV replication, and the fact that it has no host cell counterpart, make it an attractive drug development target. The recent introduction of the integrase targeted drug raltegravir has validated this enzyme as a very promising HIV/AIDS therapeutic target. Our studies on small molecule inhibitors of HIV integrase with novel bioisosteric replacement of the beta-diketo acid motive have led to the identification of novel HIV integrase inhibitors with single digit micromolar potency. We propose to undertake lead optimization to increase the potency and assess their potential to treat HIV infection. We will combine medicinal chemistry with computer-aided drug design and biological testing for potency, selectivity and toxicity. An innovative integration of docking, molecular dynamics simulations, structure-based design, chemoinformatics, pharmacophore mapping and three dimensional quantitative structure-activity relationships (3D-QSAR), parallel combinatorial synthesis, bioassays using recombinant wild type and mutant HIV integrase variants, cell culture testing against viral replication including drug resistant isolates from AIDS patients, will be applied. HIV-1 infected human peripheral blood mononuclear cell (PBMC) cultures will be used to test the ability of compounds to block HIV replication. Toxicity of compounds will be tested using uninfected PBMCs as well as CEM leukemia and Vero cells to assess therapeutic index. The success of this project will provide novel "drug- like" integrase inhibitors as preclinical HIV/AIDS drug development candidates; and increase our knowledge in the design of novel HIV integrase targeted antiviral agents. PUBLIC HEALTH RELEVANCE: This grant proposal seeks to develop new compounds for inhibiting HIV integrase to treat AIDS. The PI has discovered potent integrase inhibitors. The objectives of the grant proposal are to optimize activity and test toxicity.